Cardiac glycosides have been shown to inhibit cardiac Na, K ions-ATPase and sodium-pump activities and simultaneously increase cardiac contractile force. Since other inhibitors of the sodium-pump such as Rb ion, TT ion, and Li ion also cause positive inotropic effects, it appears that the inhibition of sodium-pump activity is causally related to the inotropic response of these agents. The events which connect sodium-pump inhibition to the enhanced cardiac contractile force will be studied by first elucidating the influence of sodium-pump inhibition on the dynamic changes which occur in intracellular cation concentrations during each cycle of contraction and relaxation and subsequently determine the influences of such ionic alterations on calcium turn-over. Additionally, the nature of the molecular interactions between cardiac glycosides and inotropic and toxic "receptors" for cardiac glycosides, and the factors and agents which modify such interactions will be studied using an in vitro model. Finally, the relationship between the inhibition of Na,K ions-ATPase in the central nervous system and the stimulation of vagal and sympathetic centers will be studied in an attempt to find an agent which has a better therapeutic index than existing cardiac glycosides.